BACKGROUND:Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein convertase that posttranslationally promotes the degradation of the low-density lipoprotein receptor (LDLR) in hepatocytes and increases plasma LDL cholesterol (LDL-C). Heterozygote gain-of-function mutations of PCSK9 are associated with the familial hypercholesterolemia phenotype, whereas loss-of-function variants are associated with reduced LDL-C concentrations and lower coronary risk. Plasma PCSK9 correlates with body mass index, triglyceridemia, total cholesterol, and LDL-C in adults, but no data are available in youth.

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Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder of chylomicron metabolism causing severe elevation of triglyceride (TG) levels (>10 mmol L−1). This condition is associated with a significant risk of recurrent acute pancreatitis (AP). AP caused by hypertriglyceridaemia (HTG) has been associated with a worse prognosis and higher mortality rates compared to pancreatitis of other aetiology. Despite its association with poor quality of life and increased lifelong risk of HTG‐AP, few healthcare providers are familiar with FCS. Because this condition is under‐recognized, the majority of FCS patients are diagnosed after age 20 often after consulting several physicians. Although other forms of severe HTG such as multifactorial chylomicronemia have been associated with high atherosclerotic cardiovascular disease (ASCVD) risk and metabolic abnormalities, ASCVD and metabolic syndrome are not usually observed in FCS patients. Because FCS is a genetic condition, the optimal diagnosis strategy remains genetic testing. The presence of bi‐allelic pathogenic mutations in LPL, APOC2, GPIHBP1, APOA5 or LMF1 genes confirms the diagnosis. However, some cases of FCS caused by autoantibodies against LPL or GPIHBP1 proteins have also been reported. Furthermore, a clinical score for the diagnosis of FCS has been proposed but needs further validation. Available treatment options to lower triglycerides such as fibrates or omega‐3 fatty acids are not efficacious in FCS patients. Currently, the cornerstone of treatment remains a lifelong very low‐fat diet, which prevents the formation of chylomicrons. Finally, inhibitors of apo C‐III and ANGPTL3 are in development and may eventually constitute additional treatment options for FCS patients.

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This article is available online at http://www.jlr.org among the most common is reduced triglyceride-rich lipoprotein (TRL) clearance by peripheral tissue. White adipose tissue (WAT) is a major regulator of TRL clearance, particularly in the postprandial state ( 2-6 ). Following a meal, dietary fat enters the circulation in the form of chylomicrons, TRL with apoB48. Effi cient clearance of chylomicrons by WAT requires three sequential steps: i ) the hydrolysis of chylomicrons by endothelial lipoprotein lipase (LPL); ii ) the uptake of LPL-generated nonesterifi ed fatty acid (NEFA) by underlying adipocytes; and iii ) the utilization or storage of NEFA ( 3, 5 ). Dietary TRL remnants and NEFA that are not cleared by peripheral tissue are then taken up by the liver for utilization and resecretion as VLDL (TRL with apoB100).Healthy WAT is able to respond promptly to postprandial signals, such as insulin increasing the hydrolysis of dietary TRL and the uptake and storage of generated NEFA, thus reestablishing the homeostasis in plasma lipids. The storage versus the release of TRL-generated NEFA in human subcutaneous WAT was reported to be almost absent in the fasting state, to increase to 100% 1 h after the ingestion of a meal, and to decrease to 10-30% 6 h after the meal ( 5 ). Accordingly, delayed plasma clearance of postprandial TRL by WAT is believed to increase the infl ux of dietary TRL remnants and NEFA into nonadipose peripheral tissues, including muscle, pancreas, and liver, inducing lipotoxicity and insulin resistance ( 6-8 ). In the liver, this also leads to increased synthesis and secretion of VLDL, which further reduces chylomicron clearance due to competitive binding to LPL ( 9-14 ). Altogether, this increases the plasma concentrations of apoB-lipoproteins, which is measured as plasma apoB and represents mostly LDL particles (>90%) ( 14-16 ). Dysfunctional WAT is thus Postprandial hypertriglyceridemia is an independent risk factor for cardiometabolic disease ( 1 ). Many factors have been implicated in the etiology of hyperlipidemia;

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